PROJECT SUMMARY Pancreas cancer is the fourth leading cause of cancer mortality in the United States, with very few effective therapeutic options. The median survival rate for resectable tumors is only 2 years, and systemic chemotherapy with gemcitabine only offers a modest survival benefit. The main characteristic of pancreas tumors that makes chemotherapy treatment difficult is the extensive stromal desmoplasia, which decreases blood perfusion, increases the intratumoral pressure and impedes the delivery of chemotherapy. Disrupting the stromal barrier would both increase perfusion and permeabilize the tumor, enhancing penetration of chemotherapy. In our initial grant period we successfully demonstrated that mechanical disruption of the stroma using pulsed high intensity focused ultrasound (pHIFU)-induced cavitation resulted in enhanced penetration of doxorubicin by up to 4.5-fold. These results were obtained in an in vivo genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma, using an optimized ultrasound-guided pHIFU small animal treatment system. The KPC model, unlike xenograft or subcutaneous models, closely recapitulates the genetic mutations, clinical symptoms and histopathology found in human pancreatic cancer. These results are readily translatable to patient treatment. In this renewal application we propose to evaluate the tumor response and survival of KPC mice treated with pHIFU and systemic administration of gemcitabine. We will then develop a new ultrasound-guided pHIFU clinical system that incorporates Bubble Doppler imaging algorithms to enable monitoring of pHIFU therapy. The system will be designed, fabricated and characterized following FDA guidelines. The main paradigm shift compared to the small animal studies is the design of ultrasound transducers that produce less focused, lower frequency (sub-MHz) HIFU beams that affect larger tissue areas and may have a different physical mechanism of cavitation nucleation compared to high- frequency, highly focused transducers used previously. We hypothesize that this change will: 1) shorten treatment duration; 2) provide deeper penetration depth; 3) allow the use of lower pHIFU pressure amplitudes and therefore improve safety. The other major innovation of this proposal is the further development of a unique cavitation mapping technique, discovered by our group during the initial grant period and termed Bubble Doppler, which enables ultrasound-based monitoring of pHIFU therapy in real-time. We will complete preclinical evaluation of the feasibility and safety of pHIFU treatments using Bubble Doppler monitoring in porcine pancreas in a series of acute and short term survival studies. In parallel, a clinical trial using this therapy device will be designed. All relevant reports will be compiled to apply for an investigational device exemption (IDE) to US FDA to conduct a clinical trial in patients with pancreatic cancer.